Method of producing 1-hydroxy-1,1-diphosphonic acid compounds

ABSTRACT

In a method for preparing 1-hydroxy-1,1-diphosphonic acid compounds of the general formula I and/or of their pharmacologically compatible salts 
                         
a compound of the formula II
 
                         
is reacted with a compound P(OSiR 5   3 ) 3-p R 6   p  and the reaction product is hydrolyzed.

BACKGROUND OF THE INVENTION

The present intention relates to a method for preparing1-hydroxy-1,1-diphosphonic acid compounds.

The concept of “drug targeting”, i.e., the targeted accumulation ofmedicaments at the location of desired action, is a strategy that hasbeen used for some time in medicine and the pharmaceutical industry. Ofspecial interest in this connection is the use of cytostatic agents, forexample, of N lost derivatives such as chlorambucil(4-(4-bis-(2-chloroethyl)amino)benzene butanoic acid) coupled to specialalkane diphosphonic acids. As a result of the high affinity of thediphosphonic acids to apatite of the bone structure, a targeted organspecificity is obtained. The compound class of such1-hydroxy-1,1-diphosphonic acid compounds, their manufacture as well astheir use as pharmacological compositions is described in Europeanpatent EP 0 170 896 B1.

According to EP 0 170896B1,1-hydroxy-1,1-diphosphonic acid compounds areproduced from carboxylic acid chlorides by reaction with H₃PO₃ in thepresence of a dehydrating agent in yields of approximately 50%.

For the pharmaceutical use, the 1-hydroxy-1,1-diphosphonic acidcompounds must have a high degree of purity; also, high yields of themanufacturing processes are desirable.

Moreover, the compounds must have a certain solubility forpharmaceutical use. The solubility of these compounds is in itself verylow; moreover, the compounds are partially hydrolytically unstable. Animproved solubility and thus a higher concentration in thepharmacological composition can be obtained, for example, by employingsalts of the corresponding compounds. According to the prior art, thecorresponding salts are produced by neutralization with the equivalentamount of the base. In this connection, the isolation of the salts isrealized by precipitation with organic solvents, for example, alcohols,by crystallization, or by solvent evaporation from the (partially)neutralized solution. However, discolored products are often obtainedwith these methods; also, the products partially decompose resulting ina reduced yield; moreover, the partially uncharacterized decompositionproducts are undesirable in particular in connection with the use in thepharmaceutical sector.

For the isolation of the salts, it is proposed in DE 198 20 974 A1 toisolate the salts by means of freeze-drying.

SUMMARY OF THE INVENTION

The present invention has the object to provide a method that isimproved in comparison to the prior art for preparing1-hydroxy-1,1-diphosphonic acid compounds, which method provides thesecompounds, for example, in higher yields.

Object of the present invention is a method for preparing1-hydroxy-1,1-diphosphonic acid compounds of the general formula Iand/or of their pharmacologically compatible salts

wherein

-   R¹ is hydrogen, OH, NO₂, Cl, F, Br, C₁–C₆ alkyl that can also be    substituted by halogen, amino, and/or aminoalky, C₁–C₆ alkoxy, aryl,    heteroaryl, a group NR³R⁴ in which R³ and R⁴ can be identical or    different and represent hydrogen, C₁–C₆alkyl, halogen-substituted    alkyl, hydroxy-C₁–C₆ alkyl,-   R² is hydrogen, halogen, amino that can also be substituted, C₁–C₆    alkyl that can also be substituted by halogen, amino, and/or    aminoalky, C₁–C₆ alkoxy, aryl, heteroaryl,-   Y O, S, or NH,-   Z C₁–C₅ alkylene that can be substituted by amino groups,-   m and n are 0 or 1, under the condition that, when n=1 then also    m=1, wherein a compound of the formula II

wherein R¹, R², Y, Z, m, and n are defined as above, is reacted with acompound of the formula IIIP(OSiR⁵ ₃)_(3-p)R⁶ _(p)  (III)wherein

-   R⁵ is a C₁–C₄ alkyl group,-   R⁶ is a C₁–C₆ alkoxy group,-   p is 0, 1, or 2,

wherein the reaction product is hydrolyzed in a known way and optionallyreacted to the salts.

The method according to the invention enables the preparation of1-hydroxy-1,1-diphosphonic acid compounds in high yields and in such apurity that the products can also be used in pharmacologicalcompositions. Also, a further reaction to form the easily soluble saltsis possible.

According to the invention, R¹ in the compounds of the formula I ishydrogen, OH, NO₂, Cl, F, Br, C₁–C₆ alkyl that can also be substitutedby halogen, amino, and/or aminoalky, C₁–C₆ alkoxy, aryl, heteroaryl, agroup NR³R⁴ in which R³ and R⁴ can be identical or different andrepresent hydrogen, C₁–C₆ alkyl, halogen-substituted alkyl,hydroxy-C₁–C₆ alkyl. In a preferred embodiment, R¹ is a NR³R⁴ group inwhich R³ and R⁴ are identical and represent a halogen-substituted C₁–C₆alkyl group, preferably, a group —CH₂—CHR⁷Cl, wherein R⁷ is hydrogen ora methyl group, preferably, hydrogen.

Preferred halogen substituents for R² are fluorine, chlorine, orbromine. Preferred alkyl moieties or alkoxy moieties for R² have notmore than 5, in particular, not more than 3, C atoms; preferably, theyare methyl or ethyl groups. The alkyl moieties or alkoxy moieties canoptionally be substituted, for example, by one or several amino groups.R² can also be an amino group, optionally substituted. In a preferredembodiment, R¹ is hydrogen, a methyl, methoxy or nitro group.

Relative to the molecule part that is bonded to the aromatic ring by Y,the moiety R¹ can be in o, m or p position. When the moiety R¹ is anamino group, this molecule part is preferably in the p position whereinR¹ is then a so-called N lost group.

According to the invention, m and n can be 0 or 1, but under thecondition that when n=1, i.e., one of the moieties O, S, or NH ispresent, then also m=1. In a preferred embodiment, n=0, i.e, the moietyY is not present. In this configuration, it is also possible that n=0.

It is especially preferred that n=0 and m=1, i.e., the alkylene group Zis directly bonded to the aromatic ring. This linear or branched oroptionally substituted moiety Z contains preferably not more than 5 Catoms, in particular, not more than 3 C atoms, wherein unbranched Cchains are preferred. As an example of possible substituents on Z anamino group should be mentioned. Preferred substituents for Z are thefollowing:

A preferred embodiment of the formula I is4-(4-(bis-(2-chloroethyl)amino)benzene)-1hydroxybutane-1,1-diphosphonicacid that is referred to, for short, as “CAD” (chlorambucil coupled to1-hydroxy-1,1-diphosphonic acid).

For preparing the compounds of the formula I, according to the inventionin a first reaction step as a starting material the carboxylic acidderivatives of the formula II are reacted with a phosphorylating agentof the formula II. The compounds of the formula II and formula III arepreferably reacted in approximately stoichiometric amounts.Stoichiometric means that the starting compounds are reactedapproximately in a molar ratio of 1:2 when the compound of the formula Idoes not contain an amino group. The molar ratio of the compounds of theformula II to the compounds of the formula III is preferablyapproximately 1:3 when the compound of the formula II contains an aminogroup.

In order to achieve excellent mixing of the reaction partners, thereaction mixture is preferably stirred.

The reaction of the compounds of the formula II with the compound of theformula III can be carried out within a wide temperature range of −30°C. to 50° C. Preferably, the reaction is carried out at a temperaturefrom 10 to 30° C. Temperatures significantly above room temperature arenot preferred because of the formation of undesirable byproducts.

In the method according to the invention, it was found to beadvantageous to dissolve the compound of the formula II first in asuitable organic solvent or to suspend it therein and to add thecompound of the formula III, either as a pure compound or also in adissolved or suspended form. The solvent for dissolving the compounds ofthe formula II and formula III can be polar or non-polar organicsolvents such as toluene, benzene, chlorobenzene, pentane, hexane,hexane, heptane, petroleum ether, diethyl ether, tetrahydrofurane

After the addition of the compounds of the formula III, it is preferredto allow the reaction mixture to react for some time. For this purpose,the temperature can be optionally increased somewhat, wherein an afterreaction at room temperature is preferred.

The reaction product obtained in the first method step by reaction ofthe compounds of the formulas II and III, can be isolated by knownmethods after completion of the reaction or can be directly furtherreacted to the diphosphonic acid, i.e., can be hydrolyzed. Preferably,before further reactions are carried out, volatile reaction (by)productsare removed in vacuum.

The hydrolysis of the reaction product obtained in the first method stepis carried out by known methods. Preferably, the reaction product isdissolved in one of the above-mentioned organic solvents and water isadded, optionally with stirring, and the compound of the formula I isformed.

The compound of the formula I can be isolated as is known in the artand, if required, can be purified in that the generally insolublereaction product is filtered to remove the solvent and, optionally, iswashed with solvent.

For use in pharmacological compositions, the compounds of the formula Iare preferably used in the form of their soluble salts. Partial salts,in which only a part of the four of the acidic protons are replaced byother cations, as well as complete salts as well as mixtures ofdifferent salts as well as mixtures of the free acids with salts can beused. Examples of pharmacologically compatible salts are alkali, earthalkali and/or ammonium salts, such as sodium, potassium, magnesium,ammonium, and substituted ammonium salts. Preferred are essentiallyneutral-reacting salts whose pH value in aqueous solution is betweenapproximately 5 and 9. Especially preferred are partially neutralizedsalts such as monosodium, disodium, and trisodium salts, and completelyneutralized sodium salts of the compounds of the formula I.

The neutralization of the compounds of the formula I can be carried outas is known in the art by reaction with the corresponding bases, as isdescribed, for example, in EP 0 170 896 A1 and in DE 198 20 974 A1.Preferably, the aqueous solutions of the corresponding alkali, earthalkali, and ammonium compounds, such as sodium, potassium, magnesium,ammonium and substituted ammonium compounds, are used, wherein anaqueous sodium hydroxide solution is preferred as a base. Usually, the1-hydroxy-1,1-diphosphonic acid compounds are reacted with equivalentamounts of the base; for example, when preparing a tetrasodium salt, thebase is added in a four-fold molar ratio relative to1-hydroxy-1,1-diphosphonic acid compounds. Correspondingly, whenpreparing the disodium salt, a two-fold molar ratio of the base is used.It was found to be advantageous when the 1-hydroxy-1,1-diphosphonic acidcompounds are added to the cold—preferably from 0° C. to roomtemperature—solution of the base. In a preferred embodiment, thereaction is carried out in an O₂-free atmosphere and the solution issubsequently allowed to warm to room temperature. The neutralizationwith alkali hydride is also possible.

The neutralization can be realized also by adding the1-hydroxy-1,1-diphosphonic acid compound to an aqueous cold sodiumcarbonate solution, wherein equivalent amounts or up to twice the amountof sodium carbonate (Na₂CO₃) is used. A further possibility of preparingthe salts resides in the use of ion exchangers.

In another preferred embodiment, for the preparation of the alkalisalts, the compound of the formula I is reacted with a correspondingalkali acetate, in particular, sodium acetate. The reaction ispreferably carried out at room temperature.

The product which is obtained from the (partial) neutralization can bedirectly further reacted after removal of the volatile reactionproducts; a difficult isolation is generally not required.

Compounds of the formula I in which R¹ is hydrogen, Me, OMe, NH₂, NO₂and R² is hydrogen, Z is a propylene group, n is 0, and m is 1, are new.

Accordingly, a further object of the present intention is a compound ofthe following formula IV

wherein R¹′=H, Me, OMe, NH₂, NO₂and a compound of the formula V

wherein R¹′=H, Me, OMe, NH₂, NO₂.

DESCRIPTION OF REFERRED EMBODIMENTS EXAMPLES Example 1

1.1 Preparation of the Acid Chlorides with SOCl₂ According to MethodsKnown from the Literature

The required preparations for working under exclusion of moisture andoxygen were carried out (dry diethyl ether, dry and oxygen-free nitrogen(gas) as an inert gas atmosphere).

1.2 Preparation of Diphosphonic Acids via Persilylated Derivatives (forR=H, Me, OMe, NO₂)

6.7 ml (appr. 20 mmol) of tris(trimethylsilyl)phosphite (Hata, T.;Sekine, M; J. Am. Chem. Soc. 96 (1974) 7363; Sekine, M; Okimoto, K;Yamada, K.: J. Org. Chem. 46 (1981) 2097) were added to a solution ofthe acid chloride (appr. 10 mmol) in 30 ml of diethyl ether, the mixturewas stirred for 1–2 hours, and the volatile components removed at 80–90°C. in water-jet pump vacuum (20 mbar). NMR (Et₂O) of the persilylatedderivatives: ³¹P: e.g. δ=3.42 (R=H), 3.65 (R=NO₂).

Water (10 ml) was added to the residue, the mixture heated understirring for 1 h at 80–90° C. and then dried in vacuum (0.1 mbar). Theresidue was then treated with 10–15 ml diethyl ether, the precipitatedmaterial was filtered, washed with a small amount of diethyl ether, anddried (for R=H, Me, NO₂). In the case of R=OMe, the residue with treatedwith ethyl acetate, washed with a minimum amount of ethyl acetate, anddried. For R=NO₂ a diphosphonic acid diethyl ether complex (1:1) wasobtained that was converted to the pure acid by heating for 2 h at80–90° C. while pumping at 0.1 mbar. Melting point diphosphonic acid R=H(C₁₀H₁₆O₇P₂, 310.18) 183–185° C. (yield 75% relative to thecorresponding acid chloride); NMR: ¹H (DMSO-d₆) δ=1.86 (m, 4H,CH₂CH₂CH₂), 2.51 (m, 2H, CH₂CO), 7.18 (m, 5H, Ph), 10.20 (5H, br, OH);³¹P (DMSO-d₆) δ=21.63 (³J_(PH)=14.0 Hz). MS: (FAB, m/z %) FAB⁺311(M⁺+H), FAB⁻309 (M⁻−H); R=Me (C₁₁H₁₈O₇P₂, 324.20) 175–177° C. (71%);NMR: ¹H (DMSO-d₆) δ=1.86 (m, 4H, CH₂CH₂CH₂), 2.24 (3H, Me), 2,44 (2H,CH₂CO), 7.04 (m, 4H, Ph), 9.06 (5H, br, OH); ³¹P (DMSO-d₆) δ=21.35(³J_(PH)=13.90 Hz). MS: (FAB, m/z %): FAB⁺325 (M⁺+H), FAB⁻323 (M⁻−H);R=OMe (C₁₁H₁₈O₈P₂, 340.20) 173–175° C. (67%); NMR: ¹H (DMSO-d₆) δ=1.88(m, 4H, CH₂CH₂CH₂), 2.54 (2H, CH₂CO), 3.75 (3H, OMe), 6.90 (2H, AB, Ph),7.10 (2H, AB, Ph), 10.15 (5H, br, OH); ³¹P (DMSO-d₆) δ=21.22(³J_(PH)=13.0 Hz). MS: (FAB, m/z %): FAB⁺341 (M⁺+H), FAB⁻339 (M⁻−H);R=NO₂ 172–174° C. (70%) (C₁₀H₁₅NO₉P₂, 355.17); NMR: ¹H (DMSO-d₆) δ=1.90(m, 4H, CH₂CH₂CH₂), 2.69 (2H, CH₂CO), 6.50 (2H, AB, Ph), 8.15 (2H, AB,Ph), 10.37 (5H, br, OH); ³¹P (DMSO-d₆) δ=21.15 (³J_(PH)=13.0 Hz). MS:(FAB, m/z %): FAB⁺356 (M⁺+H), FAB⁻354 (M⁻−H).

Example 2

2.1 Preparation of Chlorambucil Hydrochloride C₁₄H₁₉Cl₄NO [359.24]according to Firestone, R. A. et al., J. Med. Chem. 1984, 27 1037

Oxalylchloride 5.2 ml (60 mmol) was added to a stirred solution of 1.82g (appr. 6 mmol) of chlorambucil in 30 ml of methylene chloride at 0° C.together with a drop of DMF (dimethylformamide). The mixture was stirredat the same temperature for 30 minutes, then for 1.5 h at roomtemperature, and then dried under water-jet pump vacuum (20 mbar) in awater bath (40–50° C.), then at the same temperature in vacuum (0.1mbar) The yield of chlorambucil hydrochloride 2.16 g (slightly yellowsolid) was quantitative.

2.2 Preparation of Persilylated Chlorambucil Diphosphonic AcidC₂₉H₆₃Cl₂NO₇P₂Si₅[811.12]

Tris(trimethylsilyl)phosphite 6.0 ml (appr. 18 mmol) was added understirring to a suspension of the acid chloride hydrochloride (appr. 6mmol) in 30 ml diethyl ether at room temperature, stirred for 1–2 h(after 30 to 60 minutes the suspension disappeared) and the volatilecomponents were removed for 2–3 hours at 80–90° C. (0.1 mbar). Theresidue was an oily liquid. Yield 4.9 g, almost quantitative. NMR(Et₂O): ³¹P:δ=4.09.

2.3 Preparation of Chlorambucil Diphosphonic Acid C₁₄H₂₃Cl₂NO₇P₂[450.19]

To the oily liquid of 2.2 6 ml water was added. The reaction mixture wasallowed to rest for 3–4 h until the formed solid disappeared, then driedat 45–50° C. in vacuum (0.1 mbar). The remaining residue was heated inethyl acetate to reflux, then filtered, and dried in vacuum (0.1 mbar)at 45–50° C. Melting point 155–165° C., yield 2.7 g, almostquantitative. NMR: ¹H (DMSO-d₆) δ=1.80 (m, 4H, CH₂CH₂CH₂), 2.38 (m, 2H,CH₂CO), 3.66 (8H, CH₂) 6.66 (2H, AB, Ph), 6.98 (2H, AB, Ph), 9.50 (5H,br, OH); ³¹P (DMSO-d₆) δ=21.48 (³J_(PH)=14.0 Hz). MS: (FAB, m/z) FAB⁻448(M⁻−H).

2.4 Preparation of Sodium Chlorambucil Diphosphonate C₁₄H₂₂Cl₂NNaO₇P₂[472.17]

Chlorambucil diphosphonic acid (2.25 g, appr. 5 mmol) of 2.3 wereslurried in 6 ml water and 0.95 g (7 mmol) sodium acetate was added andallowed to react while constantly stirring for 15–20 hours. The whiteproduct was filtered, washed 3 times with 1 ml water and 3 times with 5ml ethanol, first dried in air, then in vacuum at 40° C. Yield 1.88 g(80%). NMR: ¹H(CF₃COOD): δ=2.20 (m, 4H, CH₂CH₂CH₂), 2.80 (m, 2H, CH₂CO),3.42 (2H, CH₂), 3.80 (2H, CH₂), 4.14 (4H, 2 CH₂), 7.54 (4H, br, Ph);³¹P(CF₃COOD): δ=22.38 (³J_(PH)=14.0 Hz). MS: (FAB, m/z %) FAB⁺23 (Na⁺);FAB⁻470 (M⁻−H).

1. A method for preparing 1-hydroxy-1,1-diphosphonic acid compounds ofthe general formula I and/or of their pharmacologically compatible salts

wherein R¹ is hydrogen, OH, NO₂, Cl, F, Br, C₁–C₆ alkyl optionallysubstituted by halogen, amino, and/or aminoalky, C₁–C₆ alkoxy, aryl,heteroaryl, a group NR³R⁴ in which R³ and R⁴ are identical or differentand represent hydrogen, C₁–C₆ alkyl, halogen-substituted alkyl,hydroxy-C₁–C₆ alkyl, R² is hydrogen, halogen, amino that is optionallysubstituted, C₁–C₆ alkyl optionally substituted by halogen, amino,and/or aminoalky, C₁–C₆ alkoxy, aryl, heteroaryl, Y O, S, or NH, Z C₁–C₅alkylene optionally substituted by amino groups, m and n are 0 or 1,under the condition that when n=1 then also m=1, the method comprisingthe steps of: a) reacting a compound of the formula II

wherein R¹, R², Y, Z, m, and n are defined as above, with a compound ofthe formula IIIP(OSiR⁵ ₃)_(3-p)R⁶ _(p)  (III) wherein R⁵ is a C₁–C₄ alkyl group; R⁶ isa C₁–C₆ alkoxy group; p is 0, 1, or 2; and b) hydrolyzing the reactionproduct of step a).
 2. The method according to claim 1, furthercomprising the step of reacting the hydrolyzed product to thepharmacologically compatible salts.
 3. The method according to claim 1,wherein the compound of the formula I is4-(4-(bis-(2-chloroethyl)amino)benzene)-1-hydroxybutane-1,1-diphosphonicacid.
 4. The method according to claim 1, wherein p is 0 in the formulaIII.
 5. The method according to claim 1, wherein in step a) thecompounds of the formula II and of the formula III are reacted inapproximately stoichiometric amounts.
 6. The method according to claim1, further comprising the step of preparing the pharmacologicallycompatible salts, wherein the compounds of the formula I are neutralizedor partially neutralized with aqueous solutions of the correspondingalkali, earth alkali, and ammonium compounds.
 7. The method according toclaim 6, wherein sodium, potassium, magnesium, ammonium, and substitutedammonium compounds are used.
 8. The method according to claim 6, whereinalkali acetate is used.
 9. A compound of the formula (IV)

wherein R¹′=H, Me, OMe, NH₂, NO₂.
 10. A compound of the formula (V)

wherein R¹′=H, Me, OMe, NH₂, NO₂.